tbuckley/cabot-search huggingface dataset:
Spatial Transcriptomics of Intraductal Papillary Mucinous Neoplasms of the Pancreas Identifies NKX6-2 as a Driver of Gastric Differentiation and Indolent Biological Potential
Authors: Marta Sans, Yuki Makino, Jimin Min, Kimal I. Rajapakshe, Michele Yip-Schneider, C. Max Schmidt, Mark W. Hurd, Jared K. Burks, Javier A. Gomez, Fredrik I. Thege, Johannes F. Fahrmann, Robert A. Wolff, Michael P. Kim, Paola A. Guerrero, Anirban Maitra
Journal: Cancer Discovery (2023)

Intraductal papillary mucinous neoplasms (IPMN) of the pancreas are bona fide precursor lesions of pancreatic ductal adenocarcinoma (PDAC). The most common subtype of IPMNs harbors a gastric foveolar-type epithelium, and these low-grade mucinous neoplasms are harbingers of IPMNs with high-grade dysplasia and cancer. The molecular underpinning of gastric differentiation in IPMNs is unknown, although identifying drivers of this indolent phenotype might enable opportunities for intercepting progression to high-grade IPMN and cancer. We conducted spatial transcriptomics on a cohort of IPMNs, followed by orthogonal and cross-species validation studies, which established the transcription factor NKX6-2 as a key determinant of gastric cell identity in low-grade IPMNs. Loss of NKX6-2 expression is a consistent feature of IPMN progression, while reexpression of Nkx6-2 in murine IPMN lines recapitulates the aforementioned gastric transcriptional program and glandular morphology. Our study identifies NKX6-2 as a previously unknown transcription factor driving indolent gastric differentiation in IPMN pathogenesis. Identification of the molecular features driving IPMN development and differentiation is critical to prevent cancer progression and enhance risk stratification. We used spatial profiling to characterize the epithelium and microenvironment of IPMN, which revealed a previously unknown link between NKX6-2 and gastric differentiation, the latter associated with indolent biological potential. See related commentary by Ben-Shmuel and Scherz-Shouval, p. 1768. This article is highlighted in the In This Issue feature, p. 1749.
Establishing severe acute respiratory infection (SARI) surveillance in a sentinel hospital, Ireland, 2021 to 2022
Authors: Melissa Brady, Roisin Duffy, Lisa Domegan, Abigail Salmon, Binita Maharjan, Cathal O'Broin, Charlene Bennett, James Christle, Jeff Connell, Laura Feeney, Nadra Nurdin, Patrick Mallon, Peter Doran, Rosa McNamara, Sarah O'Grady, Sinead McDermott, Naomi Petty-Saphon, Joan O’Donnell
Journal: Eurosurveillance (2023)

Background In 2020, due to the COVID-19 pandemic, the European Centre for Disease Prevention and Control (ECDC) accelerated development of European-level severe acute respiratory infection (SARI) surveillance. Aim We aimed to establish SARI surveillance in one Irish hospital as part of a European network E-SARI-NET. Methods We used routine emergency department records to identify cases in one adult acute hospital. The SARI case definition was adapted from the ECDC clinical criteria for a possible COVID-19 case. Clinical data were collected using an online questionnaire. Cases were tested for SARS-CoV-2, influenza and respiratory syncytial virus (RSV), including whole genome sequencing (WGS) on SARS-CoV-2 RNA-positive samples and viral characterisation/sequencing on influenza RNA-positive samples. Descriptive analysis was conducted for SARI cases hospitalised between July 2021 and April 2022. Results Overall, we identified 437 SARI cases, the incidence ranged from two to 28 cases per week (0.7–9.2/100,000 hospital catchment population). Of 431 cases tested for SARS-CoV-2 RNA, 226 (52%) were positive. Of 349 (80%) cases tested for influenza and RSV RNA, 15 (4.3%) were positive for influenza and eight (2.3%) for RSV. Using WGS, we identified Delta- and Omicron-dominant periods. The resource-intensive nature of manual clinical data collection, specimen management and laboratory supply shortages for influenza and RSV testing were challenging. Conclusion We successfully established SARI surveillance as part of E-SARI-NET. Expansion to additional sentinel sites is planned following formal evaluation of the existing system. SARI surveillance requires multidisciplinary collaboration, automated data collection where possible, and dedicated personnel resources, including for specimen management.
Cytoplasmic Polyadenylation Is an Ancestral Hallmark of Early Development in Animals
Authors: Labib Rouhana, Allison Edgar, Fredrik Hugosson, Valeria Dountcheva, Mark Q Martindale, Joseph F Ryan
Journal: Molecular Biology and Evolution (2023)

Differential regulation of gene expression has produced the astonishing diversity of life on Earth. Understanding the origin and evolution of mechanistic innovations for control of gene expression is therefore integral to evolutionary and developmental biology. Cytoplasmic polyadenylation is the biochemical extension of polyadenosine at the 3'-end of cytoplasmic mRNAs. This process regulates the translation of specific maternal transcripts and is mediated by the Cytoplasmic Polyadenylation Element-Binding Protein family (CPEBs). Genes that code for CPEBs are amongst a very few that are present in animals but missing in nonanimal lineages. Whether cytoplasmic polyadenylation is present in non-bilaterian animals (i.e., sponges, ctenophores, placozoans, and cnidarians) remains unknown. We have conducted phylogenetic analyses of CPEBs, and our results show that CPEB1 and CPEB2 subfamilies originated in the animal stem lineage. Our assessment of expression in the sea anemone, Nematostella vectensis (Cnidaria), and the comb jelly, Mnemiopsis leidyi (Ctenophora), demonstrates that maternal expression of CPEB1 and the catalytic subunit of the cytoplasmic polyadenylation machinery (GLD2) is an ancient feature that is conserved across animals. Furthermore, our measurements of poly(A)-tail elongation reveal that key targets of cytoplasmic polyadenylation are shared between vertebrates, cnidarians, and ctenophores, indicating that this mechanism orchestrates a regulatory network that is conserved throughout animal evolution. We postulate that cytoplasmic polyadenylation through CPEBs was a fundamental innovation that contributed to animal evolution from unicellular life.
Risk Factors for Progression and Toxic Effects After Preoperative Stereotactic Radiosurgery for Patients With Resected Brain Metastases
Authors: Roshan S. Prabhu, Tobi Akinyelu, Zachary K. Vaslow, Jennifer K. Matsui, Neda Haghighi, Tu Dan, Mark V. Mishra, Erin S. Murphy, Susan Boyles, Haley K. Perlow, Joshua D. Palmer, Cristian Udovicich, Toral R. Patel, Zabi Wardak, Graeme F. Woodworth, Alexander Ksendzovsky, Kailin Yang, Samuel T. Chao, Anthony L. Asher, Stuart H. Burri
Journal: JAMA Oncology (2023)

Preoperative stereotactic radiosurgery (SRS) has been demonstrated as a feasible alternative to postoperative SRS for resectable brain metastases (BMs) with potential benefits in adverse radiation effects (AREs) and meningeal disease (MD). However, mature large-cohort multicenter data are lacking.
Changes to Primary End Points in Randomized Clinical Trials on Immune Checkpoint Inhibitors in Urothelial, Renal Cell, and Lung Cancers
Authors: Anke Richters, Hilin Yildirim, Christopher M. Booth, Francisco E. Vera Badillo, Lambertus A. L. M. Kiemeney, Katja K. H. Aben
Journal: JAMA Oncology (2023)

This systematic review investigates how often and to what extent primary end points are changed and reported in immune checkpoint inhibitor clinical trials.
Clinical and Genomic Characteristics of Patients with Hormone Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Negative Metastatic Breast Cancer Following Progression on Cyclin-Dependent Kinase 4 and 6 Inhibitors
Authors: Xi Rao, Yongmei Chen, Julie Beyrer, Emily Nash Smyth, Claudia Morato Guimaraes, Lacey M. Litchfield, Lee Bowman, Garreth W. Lawrence, Amit Aggarwal, Fabrice Andre
Journal: Clinical Cancer Research (2023)

We explored the clinical and genomic characteristics of hormone receptor-positive (HR+), HER2-negative (HER2-) metastatic breast cancer (MBC) after progression on cyclin-dependent kinase 4 and 6 inhibitors (CDK4 and 6i) ± endocrine therapy (ET) to understand potential resistance mechanisms that may aid in identifying treatment options.
A commentary on “comparison of surgical outcomes and learning curve for robotic versus laparoscopic living donor hepatectomy: a retrospective cohort study” (int j surg 2022;108:107000)
Authors: Dingwei Xu, Jie Huang
Journal: International Journal of Surgery (2023)

Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Kunming Medical University, Kunming 650101, Yunnan names (spelled out in full) of all authors, and the institutions with which they are affiliated; indicate all affiliations with a superscripted lowercase letter after the author’s name and in front of the appropriate affiliation Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article. Published online ■ ■ *Corresponding author. Address: Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Kunming Medical University, Kunming 650101, Yunnan, 243 Dianmian Avenue,Wuhua District, Kunming city, Yunnan, China,650101, fax numbers:+86-087165351281. E-mail address: [email protected] (J. Huang). This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0/
Intranasal esketamine combined with oral midazolam provides adequate sedation for outpatient pediatric dental procedures：a prospective cohort study
Authors: Jing Wang, Jie Zeng, Nan Zhao, Silu Chen, Zhong Chen, Jingrong Liao, Haosong Ran, Cong Yu
Journal: International Journal of Surgery (2023)

Severe dental phobia or failure to cooperate with treatment are very common in outpatient pediatric dentistry. Personalized and appropriate noninvasive anesthesia methods can save medical expenses, improve treatment efficiency, reduce the anxiety of children, and improve the satisfaction of nursing staff. Currently, there is little conclusive evidence for noninvasive moderate sedation strategies in pediatric dental surgery.The trial was conducted from May 2022 to September 2022. Each child was first given midazolam oral solution 0.5 mg·kg -1 , and when the Modified Observer's Assessment of Alertness and Sedation score reached 4, a biased coin design up-down method was used to adjust the dose of esketamine. The primary outcome was the ED 95 and 95% CI of intranasal esketamine hydrochloride with midazolam 0.5 mg·kg -1 . Secondary outcomes included the onset time of sedation, treatment and awakening times, and the incidence of adverse events.A total of 60 children were enrolled; 53 children were successfully sedated but 7 were not. The ED 95 of intranasal esketamine with 0.5 mg·kg -1 midazolam oral liquid for the treatment of dental caries was 1.99 mg·kg -1 (95% CI 1.95-2.01 mg·kg -1 ). The mean onset time of sedation for all patients was 43.7±6.9 min. 15.0 (10-24.0) min for examination and 89.4±19.5 min for awakening. The incidence of intraoperative nausea and vomiting was 8.3%. Adverse reactions such as transient hypertension and tachycardia occurred during the operations.The ED 95 of intranasal esketamine with 0.5 mg·kg -1 midazolam oral liquid for the outpatient pediatric dentistry procedure under moderate sedation was 1.99 mg·kg -1 . For children aged 2-6 years with dental anxiety who require dental surgery, anesthesiologists may consider using midazolam oral solution combined with esketamine nasal drops for noninvasive sedation after a preoperative anxiety scale evaluation.
Necessity and time interval of regional lymph node dissection for malignant melanoma with positive sentinel lymph node biopsy-does the time interval between sentinel lymph node biopsy and completion lymph node dissection affect outcome in malignant melanoma? a retrospective cohort study-a commentary
Authors: Jingxiu Chai, Zubing Mei, Yuchong Chen
Journal: International Journal of Surgery (2023)

aDepartment of Dermatologic Surgery DivisionI, Shanghai Skin Disease Hospital Affiliated to Tongji University, Shanghai 200443, China bDepartment of Anorectal Surgery, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, 201203, Shanghai, China Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article. Published online ■ ■ *Corresponding author. Address: Department of Dermatologic Surgery DivisionI, Shanghai Skin Disease Hospital Affiliated to Tongji University, Shanghai 200443, China; Department of Anorectal Surgery, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine; Shanghai, China. E-mail address: [email protected] (Z. Mei). *Corresponding author. Address: Department of Dermatologic Surgery DivisionI, Shanghai Skin Disease Hospital Affiliated to Tongji University, No. 1278, Baode Road, Jing’an District, Shanghai, 200443, China. E-mail address: [email protected].(Y. Chen). This is an open access article distributed under the Creative Commons Attribution-ShareAlike License 4.0, which allows others to remix, tweak, and build upon the work, even for commercial purposes, as long as the author is credited and the new creations are licensed under the identical terms. http://creativecommons.org/licenses/by-sa/4.0/
A CAPTIVATEing Analysis for Higher-Risk CLL
Authors: Kerry A. Rogers
Journal: Clinical Cancer Research (2023)

In an exploratory analysis of the phase II CAPTIVATE study, previously untreated patients with chronic lymphocytic leukemia with a higher-risk feature of immune globulin heavy chain variable (IGHV) unmutated status, del(17p), and/or TP53 mutation had similar efficacy and safety outcomes compared with patients without a higher-risk feature when treated with fixed-duration ibrutinib and venetoclax. See related article by Allan et al., p. 2593.
Place of Death From Cancer in US States With vs Without Palliative Care Laws
Authors: Main Lin Quan Vega, Stanford T. Chihuri, Deven Lackraj, Komal Patel Murali, Guohua Li, May Hua
Journal: JAMA Network Open (2023)

Importance In the US, improving end-of-life care has become increasingly urgent. Some states have enacted legislation intended to facilitate palliative care delivery for seriously ill patients, but it is unknown whether these laws have any measurable consequences for patient outcomes. Objective To determine whether US state palliative care legislation is associated with place of death from cancer. Design, Setting, and Participants This cohort study with a difference-in-differences analysis used information about state legislation combined with death certificate data for 50 US states (from January 1, 2005, to December 31, 2017) for all decedents who had any type of cancer listed as the underlying cause of death. Data analysis for this study occurred between September 1, 2021, and August 31, 2022. Exposures Presence of a nonprescriptive (relating to palliative and end-of-life care without prescribing particular clinician actions) or prescriptive (requiring clinicians to offer patients information about care options) palliative care law in the state-year where death occurred. Main Outcomes and Measures Multilevel relative risk regression with state modeled as a random effect was used to estimate the likelihood of dying at home or hospice for decedents dying in state-years with a palliative care law compared with decedents dying in state-years without such laws. Results This study included 7 547 907 individuals with cancer as the underlying cause of death. Their mean (SD) age was 71 (14) years, and 3 609 146 were women (47.8%). In terms of race and ethnicity, the majority of decedents were White (85.6%) and non-Hispanic (94.1%). During the study period, 553 state-years (85.1%) had no palliative care law, 60 state-years (9.2%) had a nonprescriptive palliative care law, and 37 state-years (5.7%) had a prescriptive palliative care law. A total of 3 780 918 individuals (50.1%) died at home or in hospice. Most decedents (70.8%) died in state-years without a palliative care law, while 15.7% died in state-years with a nonprescriptive law and 13.5% died in state-years with a prescriptive law. Compared with state-years without a palliative care law, the likelihood of dying at home or in hospice was 12% higher for decedents in state-years with a nonprescriptive palliative care law (relative risk, 1.12 [95% CI 1.08-1.16]) and 18% higher for decedents in state-years with a prescriptive palliative care law (relative risk, 1.18 [95% CI, 1.11-1.26]). Conclusions and Relevance In this cohort study of decedents from cancer, state palliative care laws were associated with an increased likelihood of dying at home or in hospice. Passage of state palliative care legislation may be an effective policy intervention to increase the number of seriously ill patients who experience their death in such locations.
<i>Haemophilus influenzae</i> and <i>Moraxella catarrhalis</i> in sputum of severe asthma with inflammasome and neutrophil activation
Authors: Ali Versi, Fransiskus Xaverius Ivan, Mahmoud I. Abdel‐Aziz, Stewart Bates, John Riley, Frederic Baribaud, Nazanin Zounemat Kermani, Paolo Montuschi, Sven‐Erik Dahlen, Ratko Djukanovic, Peter Sterk, Anke H. Maitland‐Van Der Zee, Sanjay H. Chotirmall, Peter Howarth, Ian M. Adcock, Kian Fan Chung
Journal: Allergy (2023)

Because of altered airway microbiome in asthma, we analysed the bacterial species in sputum of patients with severe asthma.Whole genome sequencing was performed on induced sputum from non-smoking (SAn) and current or ex-smoker (SAs/ex) severe asthma patients, mild/moderate asthma (MMA) and healthy controls (HC). Data were analysed by asthma severity, inflammatory status and transcriptome-associated clusters (TACs).α-diversity at the species level was lower in SAn and SAs/ex, with an increase in Haemophilus influenzae and Moraxella catarrhalis, and Haemophilus influenzae and Tropheryma whipplei, respectively, compared to HC. In neutrophilic asthma, there was greater abundance of Haemophilus influenzae and Moraxella catarrhalis and in eosinophilic asthma, Tropheryma whipplei was increased. There was a reduction in α-diversity in TAC1 and TAC2 that expressed high levels of Haemophilus influenzae and Tropheryma whipplei, and Haemophilus influenzae and Moraxella catarrhalis, respectively, compared to HC. Sputum neutrophils correlated positively with Moraxella catarrhalis and negatively with Prevotella, Neisseria and Veillonella species and Haemophilus parainfluenzae. Sputum eosinophils correlated positively with Tropheryma whipplei which correlated with pack-years of smoking. α- and β-diversities were stable at one year.Haemophilus influenzae and Moraxella catarrhalis were more abundant in severe neutrophilic asthma and TAC2 linked to inflammasome and neutrophil activation, while Haemophilus influenzae and Tropheryma whipplei were highest in SAs/ex and in TAC1 associated with highest expression of IL-13 type 2 and ILC2 signatures with the abundance of Tropheryma whipplei correlating positively with sputum eosinophils. Whether these bacterial species drive the inflammatory response in asthma needs evaluation.
Thyroid Cancers Exhibit Oncogene-Enhanced Macropinocytosis that Is Restrained by IGF1R and Promote Albumin–Drug Conjugate Response
Authors: Huiyu Hu, Thomas S.C. Ng, Mikyung Kang, Ella Scott, Ran Li, Jeremy M. Quintana, Dylan Matvey, Venkata R. Vantaku, Ralph Weissleder, Sareh Parangi, Miles A. Miller
Journal: Clinical Cancer Research (2023)

Abstract Purpose: Oncogene-driven macropinocytosis fuels nutrient scavenging in some cancer types, yet whether this occurs in thyroid cancers with prominent MAPK–ERK and PI3K pathway mutations remains unclear. We hypothesized that understanding links between thyroid cancer signaling and macropinocytosis might uncover new therapeutic strategies. Experimental Design: Macropinocytosis was assessed across cells derived from papillary thyroid cancer (PTC), follicular thyroid cancer (FTC), non-malignant follicular thyroid, and aggressive anaplastic thyroid cancer (ATC), by imaging fluorescent dextran and serum albumin. The impacts of ectopic BRAFV600E and mutant RAS, genetic PTEN silencing, and inhibitors targeting RET, BRAF, and MEK kinases were quantified. BrafV600E p53−/− ATC tumors in immunocompetent mice were used to measure efficacy of an albumin–drug conjugate comprising microtubule-destabilizing monomethyl auristatin E (MMAE) linked to serum albumin via a cathepsin-cleavable peptide (Alb-vc-MMAE). Results: FTC and ATC cells showed greater macropinocytosis than non-malignant and PTC cells. ATC tumors accumulated albumin at 8.8% injected dose per gram tissue. Alb-vc-MMAE, but not MMAE alone, reduced tumor size by &amp;gt;90% (P &amp;lt; 0.01). ATC macropinocytosis depended on MAPK/ERK activity and nutrient signaling, and increased by up to 230% with metformin, phenformin, or inhibition of IGF1Ri in monoculture but not in vivo. Macrophages also accumulated albumin and express the cognate IGF1R ligand, IGF1, which reduced ATC responsiveness to IGF1Ri. Conclusions: These findings identify regulated oncogene-driven macropinocytosis in thyroid cancers and demonstrate the potential of designing albumin-bound drugs to efficiently treat them.
The effect of vitamin D supplementation on the gut microbiome in older Australians – Results from analyses of the D-Health Trial
Authors: Hai Pham, Mary Waterhouse, Sabbir Rahman, Catherine Baxter, Briony Duarte Romero, Donald S. A. McLeod, Peter R. Ebeling, Dallas R English, Gunter Hartel, Rachel L. O’Connell, Jolieke C. van der Pols, Alison J. Venn, Penelope M. Webb, David C. Whiteman, Flavia Huygens, Rachel E. Neale
Journal: Gut Microbes (2023)

Observational studies suggest a link between vitamin D and the composition of the gut microbiome, but there is little evidence from randomized controlled trials of vitamin D supplementation. We analyzed data from the D-Health Trial, a randomized, double-blind, placebo-controlled trial. We recruited 21,315 Australians aged 60–84 y and randomized them to 60,000 IU of vitamin D3 or placebo monthly for 5 y. Stool samples were collected from a sample of 835 participants (417 in the placebo and 418 in the vitamin D group) approximately 5 y after randomization. We characterized the gut microbiome using 16S rRNA gene sequencing. We used linear regression to compare alpha diversity indices (i.e. Shannon index (primary outcome), richness, inverse Simpson index), and the ratio of Firmicutes to Bacteroidetes between the two groups. We analyzed between-sample (beta) diversity (i.e. Bray Curtis distance and UniFrac index) using principal coordinate analysis and used PERMANOVA to test for significant clustering according to randomization group. We also assessed the difference in the abundance of the 20 most abundant genera between the two groups using negative binomial regression model with adjustment for multiple testing. Approximately half the participants included in this analysis were women (mean age 69.4 y). Vitamin D supplementation did not alter the Shannon diversity index (mean 3.51 versus 3.52 in the placebo and vitamin D groups, respectively, p = 0.50). Similarly, there was little difference between the groups for other alpha diversity indices, the abundance of different genera, and the Firmicutes-to-Bacteroidetes ratio. We did not observe clustering of bacterial communities according to randomization group. In conlusion, monthly doses of 60,000 IU of vitamin D supplementation for 5 y did not alter the composition of the gut microbiome in older Australians.